CN105348220B - A kind of synthetic method of hydrobromic acid Vortioxetine - Google Patents

A kind of synthetic method of hydrobromic acid Vortioxetine Download PDF

Info

Publication number
CN105348220B
CN105348220B CN201510758811.2A CN201510758811A CN105348220B CN 105348220 B CN105348220 B CN 105348220B CN 201510758811 A CN201510758811 A CN 201510758811A CN 105348220 B CN105348220 B CN 105348220B
Authority
CN
China
Prior art keywords
vortioxetine
hydrobromic acid
dimethyl
dimethylphenyl
nitrobenzene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510758811.2A
Other languages
Chinese (zh)
Other versions
CN105348220A (en
Inventor
孟庆亮
闫海英
韩立霞
李国庆
郭明
刘怀振
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong Chuan Cheng Medicine Co.,Ltd.
Original Assignee
SHANDONG CHUANCHENG PHARMACEUTICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SHANDONG CHUANCHENG PHARMACEUTICAL Co Ltd filed Critical SHANDONG CHUANCHENG PHARMACEUTICAL Co Ltd
Priority to CN201510758811.2A priority Critical patent/CN105348220B/en
Publication of CN105348220A publication Critical patent/CN105348220A/en
Application granted granted Critical
Publication of CN105348220B publication Critical patent/CN105348220B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

The invention provides a kind of synthetic method of hydrobromic acid Vortioxetine, first by 2 nitro thiophenols and 2, the reaction of 4 dimethyl iodobenzenes obtains (2, the 4 3,5-dimethylphenyl sulfenyls of intermediate 2）Nitrobenzene, the intermediate obtains 2 (2,4 3,5-dimethylphenyl sulfenyls by reduction）Nitrobenzene, then with two (2 chloroethyls）Amine hydrochlorate ring-closure reaction obtains Vortioxetine, finally obtains hydrobromic acid Vortioxetine into salt with hydrobromic acid.The total recovery of hydrobromic acid Vortioxetine is up to 65% in the present invention, and the technique has initiation material cheap and easy to get, the simple advantage of synthesis technique, meets industrialized production requirement.

Description

A kind of synthetic method of hydrobromic acid Vortioxetine
Technical field
The invention belongs to organic drug synthesis field, and in particular to a kind of synthetic method of hydrobromic acid Vortioxetine.
Background technology
Vortioxetine, English entitled Vortioxetine, chemistry is entitled：1- [2- (2,4- 3,5-dimethylphenyl sulfenyl)-benzene Base] piperazine is by Lundbeck drugmaker of Denmark (Lundbeck）With Japanese Takeda Pharmaceutical Company Limited (Takeda）One researched and developed jointly New antidepressant medicine is planted, the medicine acquisition FDA approvals of in September, 2013 are listed, and trade name is Brintellix, 2013 December, the medicine is ratified to list in European Union.Its chemical structural formula is as follows：
。
The medicine is played a role by 2 kinds of combining for mechanism of action：Receptor active is adjusted and reuptake suppresses.In vitro study table Bright, Vortioxetine is 5-HT3 and 5-HT7 receptor antagonists, 5-HT1B acceptor portion agonists, 5-HT1A receptor agonisms Agent, 5- hydroxytryptamines transport protein (SERT) inhibitor.Internal non-clinical study shows that it is specific that Vortioxetine can strengthen brain Regional nerve mediator --- thrombocytin, norepinephrine, dopamine, acetylcholine, the level of histamine, for treating adult's weight Property depressive disorder.
Hydrobromic acid Vortioxetine compound patent WO03029232 applied on October 2nd, 2002.The hydrogen reported in patent The synthetic route of bromic acid Vortioxetine is as follows：
Method 1
Original grinds the synthetic route of the patent WO03029232 reports of Lundbeck pharmaceutical applications, with o-dichlorohenzene, piperazine and 2,4- Dimethyl bromobenzene is Material synthesis, and the route yield is very low, and severe reaction conditions, expensive raw material price used, experiment Complex operation, is unfavorable for industrialized production.
Method 2
Lundbeck pharmacy reports a synthetic route in patent WO2007144005, and the route is with 2,4- dimethyl benzene sulphur Phenol, adjacent bromo-iodobenzene, piperazine are that initiation material synthesizes Vortioxetine, and the route raw material is easy to get, and yield is higher, but product purity compared with Low, impurity is more.
Method 3
Patent WO2007144005 also reported an other synthetic route, similar with method 2, and the route uses Boc- piperazines Piperazine replaces piperazine, reduces the generation of accessory substance.
Method 4
Patent WO2013102573 reports the synthetic route of a Vortioxetine, and the route uses the method treated different things alike, Yield is higher, and reaction only needs a step, but product purity is relatively low, is not easily purified.
In summary expensive palladium catalyst, and Phosphine ligands have been used in several synthetic routes, synthetic method, have been reacted Condition is more harsh, is unfavorable for industrialized production.
The content of the invention
The purpose of the present invention is to overcome the deficiencies in the prior art and provide a kind of synthetic method of hydrobromic acid Vortioxetine, should Process route is simple, and raw material is cheap and easy to get, and reaction condition is gentle, and yield is higher, is adapted to industrialized production.
A kind of synthetic method of hydrobromic acid Vortioxetine, comprises the following steps：
Step 1, ortho-nitrophenyl thiophenol and 2,4- dimethyl halogeno-benzene are condensed to yield 2- (2,4- bis- in the presence of acid binding agent Aminomethyl phenyl sulfenyl）Nitrobenzene；
Step 2,2- (2,4- 3,5-dimethylphenyl sulfenyls）Nitrobenzene obtains 2- (2,4- dimethyl through reduction in acid condition Phenylsulfartyl）Aniline；
Step 3,2- (2,4- 3,5-dimethylphenyl sulfenyls）Aniline and two (2- chloroethyls）Amine hydrochlorate cyclization obtains fertile for west Spit of fland；
Step 4, Vortioxetine produces hydrobromic acid Vortioxetine with hydrobromic acid into salt.
Further, acid binding agent used is sodium hydride, calcium hydride or lithium hydride, preferably sodium hydride in step 1；It is used molten Agent is tetrahydrofuran, 2- methyltetrahydrofurans or dioxane, preferably tetrahydrofuran.
In step 1, it is necessary to carry out being evaporated off at solution plus toluene and water progress extraction successively to reactant after reaction terminates Reason.
In step 1,2,4- dimethyl halogeno-benzenes are selected from 2,4- dimethyl iodobenzene or 2,4- dimethyl bromobenzene.
In step 1, the molar ratio range of ortho-nitrophenyl thiophenol, 2,4- dimethyl halogeno-benzene and acid binding agent is 1：（0.7~ 1.4）：（0.8~1.5）.
In step 2, reducing agent used is iron, zinc or tin；The acid condition is ammonium chloride solution.
In step 2,2- (2,4- 3,5-dimethylphenyl sulfenyls）The molar ratio range of nitrobenzene and reducing agent is 1：2~6, reaction 40~70 DEG C of temperature, 1~10 hour reaction time.
Solvent for use is toluene, dimethylbenzene or acetonitrile in step 3.
2- (2,4- 3,5-dimethylphenyl sulfenyls in step 3）Aniline and two (2- chloroethyls）The mol ratio of amine hydrochlorate is 1： 0.8~1.2.
In one embodiment, synthetic route of the invention is shown below：
The synthetic route of the present invention has reaction condition gentle, and raw material is easy to get, and product yield, purity are higher, is adapted to work The advantages of industry metaplasia is produced.
Embodiment
The embodiment of form, remakes further specifically to the above of the invention by the following examples It is bright, but this should not be interpreted as to the scope of above-mentioned theme of the invention be only limitted to following example, it is all based on the present invention it is above-mentioned in Hold realized technology and belong to the scope of the present invention.
The 2- of embodiment 1 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of nitrobenzene
Ortho-nitrophenyl thiophenol (14.5g, 0.1mol), 2,4- dimethyl iodine are added into dry tetra- mouthfuls of reaction bulbs of 250mL Benzene (25.5g, 1.1eq) and tetrahydrofuran 145mL, stirring is lower to add sodium hydride (3.6g, 1.5eq), and room temperature reaction 2 is small When.Reaction terminates, and revolving removes solvent, adds toluene 145mL, water 145mL, and extraction point liquid, toluene layer adds anhydrous sodium sulfate Dry, then activated carbon decolorizing steams solvent, obtain tan solid 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene 23.2g, yield 89.6%, purity 99.5%.MS(m/z): 260[M+H]+；1H NMR(400 MHz, CDCl3)δ: 8.24(dd, J=8.2,1.3Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.33~7.28 (m, 1H), 7.22~7.15 (m, 2H), 7.11(d, J=7.8 Hz, 1H), 6.72 (dd, J=8.2、1.1 Hz, 1H), 2.40(s, 3H), 2.31(s, 3H)。
The 2- of embodiment 2 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of nitrobenzene
Ortho-nitrophenyl thiophenol (14.5g, 0.1mol), 2,4- dimethyl are added into dry tetra- mouthfuls of reaction bulbs of 250mL Bromobenzene (20.4g, 1.1eq) and tetrahydrofuran 145mL, stirring is lower to add sodium hydride (3.6g, 1.5eq）, react at room temperature 2 small When.Reaction terminates, and revolving removes solvent, adds toluene 145mL, water 145mL, and extraction point liquid, toluene layer adds anhydrous sodium sulfate Dry, then activated carbon decolorizing steams solvent, obtain tan solid 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene 20.8g, yield 80.3%, purity 99.4%.
The 2- of embodiment 3 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of nitrobenzene
Ortho-nitrophenyl thiophenol (14.5g, 0.1mol), 2,4- dimethyl are added into dry tetra- mouthfuls of reaction bulbs of 250mL Iodobenzene (25.5g, 1.1eq) and tetrahydrofuran 145mL, stirring is lower to add calcium hydride (6.15g, 1.5eq), room temperature reaction 2 Hour.Reaction terminates, and revolving removes solvent, adds toluene 145mL, water 145mL, and extraction point liquid, toluene layer adds anhydrous slufuric acid Sodium is dried, and then activated carbon decolorizing steams solvent, obtain tan solid 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene 21.3g, yield 82.1%, purity 99.0%.
The 2- of embodiment 4 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of nitrobenzene
Ortho-nitrophenyl thiophenol (14.5g, 0.1mol), 2,4- dimethyl are added into dry tetra- mouthfuls of reaction bulbs of 250mL Iodobenzene (25.5g, 1.1eq) and tetrahydrofuran 145mL, stirring is lower to add lithium hydride (1.2g, 1.5eq), and room temperature reaction 2 is small When.Reaction terminates, and revolving removes solvent, adds toluene 145mL, water 145mL, and extraction point liquid, toluene layer adds anhydrous sodium sulfate Dry, then activated carbon decolorizing steams solvent, obtain tan solid 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene 21.9g, yield 84.4%, purity 98.7%.
The 2- of embodiment 5 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of nitrobenzene
Ortho-nitrophenyl thiophenol (14.5g, 0.1mol), 2,4- dimethyl are added into dry tetra- mouthfuls of reaction bulbs of 250mL Iodobenzene (25.5g, 1.1eq) and dioxane 145mL, stirring is lower to add sodium hydride (3.6g, 1.5eq）, react at room temperature 2 small When.Reaction terminates, and revolving removes solvent, adds toluene 145mL, water 145mL, and extraction point liquid, toluene layer adds anhydrous sodium sulfate Dry, then activated carbon decolorizing steams solvent, obtain tan solid 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene 20.3g, yield 78.3%, purity 98.1%.
The 2- of embodiment 6 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of nitrobenzene
Ortho-nitrophenyl thiophenol (14.5g, 0.1mol), 2,4- dimethyl are added into dry tetra- mouthfuls of reaction bulbs of 250mL Iodobenzene (25.5g, 1.1eq) and 2- methyltetrahydrofuran 145mL, stirring is lower to add sodium hydride (3.6g, 1.5eq）, room temperature is anti- Answer 2 hours.Reaction terminates, and revolving removes solvent, adds toluene 145mL, water 145mL, and extraction divides liquid, and toluene layer adds anhydrous Sodium sulphate is dried, and then activated carbon decolorizing steams solvent, obtain tan solid 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitre Base benzene 21.2g, yield 81.6%, purity 98.6%.
The 2- of embodiment 7 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of aniline
Into tetra- mouthfuls of reaction bulbs of 250mL add 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene (20.7g, 0.08mol), ammonium chloride (34.2g, 0.64mol）Aqueous solution 70mL, iron powder (17.9g, 0.32mol), ethanol 130mL, rise Temperature is reacted 4-5 hours to 50-60 DEG C, and filtering, concentration removes solvent, and residue recrystallizes to obtain off-white powder with isopropyl ether 2- (2,4- 3,5-dimethylphenyl sulfenyl) aniline 16.9g, yield 92.2%, purity 99.1%, MS (m/z): 230[M+H]+；1H NMR(400 MHz, CDCl3)δ: 7.35(dd, J=7.7、1.5 Hz, 1H),7.21(td, J=7.7、1.5 Hz, 1H), 7.01(s, 1H), 6.86(d,J=8.0 Hz, 1H), 6.81(dd, J=8.0、1.1 Hz, 1H), 6.76(dd,J= 12.1、4.5 Hz, 2H), 4.08(s, 2H), 2.40(s, 3H), 2.27(s, 3H)。
The 2- of embodiment 8 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of aniline
Into tetra- mouthfuls of reaction bulbs of 250mL add 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene (20.7g, 0.08mol), Ammonium chloride (34.2g, 0.64mol）Aqueous solution 70mL, tin (37.9g, 0.32mol), ethanol 130mL is warming up to 50-60 DEG C, react 4-5 hours, filtering, concentration removes solvent, residue recrystallizes to obtain off-white powder 2- (2,4- diformazans with isopropyl ether Base phenylsulfartyl) aniline 16.0g, yield 87.3%, purity 98.9%.
The 2- of embodiment 9 (2,4- 3,5-dimethylphenyl sulfenyls）The synthesis of aniline
Into tetra- mouthfuls of reaction bulbs of 250mL add 2- (2,4- 3,5-dimethylphenyl sulfenyl) nitrobenzene (20.7g, 0.08mol), Ammonium chloride (34.2g, 0.64mol）Aqueous solution 70mL, zinc (20.9g, 0.32mol), ethanol 130mL is warming up to 50-60 DEG C, react 4-5 hours, filtering, concentration removes solvent, residue recrystallizes to obtain off-white powder 2- (2,4- diformazans with isopropyl ether Base phenylsulfartyl) aniline 16.6g, yield 90.5%, purity 99.2%.
The synthesis of the hydrobromic acid Vortioxetine of embodiment 10
By 2- (2,4- 3,5-dimethylphenyl sulfenyl) aniline (13.7g, 0.06mol), two (2- chloroethyls) amine hydrochlorates (11.0g, 0.06mol）Add in tetra- mouthfuls of reaction bulbs of 250mL, add toluene (80mL), nitrogen protection is heated to reflux stirring anti- It should stay overnight, be cooled to 60 DEG C, concentration removes solvent, residue adds water (80 mL), ethyl acetate (80mL）Extract and separate, point From organic layer, washed with saturated nacl aqueous solution (20 mL), with anhydrous sodium sulfate drying, activated carbon decolorizing, filtering, filtrate 48% hydrobromic acid of middle dropwise addition (about 10 mL) is adjusted to pH 1~2, stirs, and separates out solid.Filtering, drying, obtains off-white powder 17.8g, yield 78.3%, purity 99.3%, 230.2~232.1 DEG C of mp.MS(m/z): 299[M+H]+；1H NMR(400 MHz, CDCl3+D2O): 7.32(d, J=7.8 Hz, 1H), 7.15(s,1H), 7.09(d, J=3.9 Hz, 2H),7.03 (d, J=7.2 Hz, 1H), 6.99~6.85 (m, 1H), 6.54 (d, J=7.8 Hz, 1H), 3.46 (dd, J=15.8, 5.4 Hz, 8H), 2.33(d,J=24.5 Hz, 6H)。
The synthesis of the hydrobromic acid Vortioxetine of embodiment 11
By 2- (2,4- 3,5-dimethylphenyl sulfenyl) aniline (13.7g, 0.06mol), two (2- chloroethyls) amine hydrochlorates (11.0g, 0.06mol) is added in tetra- mouthfuls of reaction bulbs of 250mL, adds acetonitrile (80mL), and nitrogen protection is heated to reflux stirring anti- It should stay overnight, be cooled to 60 DEG C, add water (80 mL).Divide liquid, aqueous layer with ethyl acetate (30 mL × 2) is extracted, and is merged organic Layer, is washed with saturated nacl aqueous solution (20 mL), and with anhydrous sodium sulfate drying, activated carbon decolorizing is filtered, is added dropwise in filtrate 48% hydrobromic acid (about 10 mL) is adjusted to pH 1~2, stirring, separates out solid.Filtering, drying, obtains off-white powder 16.3g, Yield 71.9%, purity 99.1%.
The synthesis of the hydrobromic acid Vortioxetine of embodiment 12
By 2- (2,4- 3,5-dimethylphenyl sulfenyl) aniline (13.7g, 0.06mol), two (2- chloroethyls) amine hydrochlorates (11.0g, 0.06mol) is added in tetra- mouthfuls of reaction bulbs of 250mL, adds dimethylbenzene (80mL), and nitrogen protection is heated to reflux stirring Reaction is stayed overnight, and is cooled to 60 DEG C, adds water (80 mL).Divide liquid, aqueous layer with ethyl acetate (30 mL × 2) is extracted, is associated with Machine layer, is washed with saturated nacl aqueous solution (20 mL), and with anhydrous sodium sulfate drying, activated carbon decolorizing is filtered, dripped in filtrate Plus 48% hydrobromic acid (about 10 mL) be adjusted to pH 1~2, stir, separate out solid.Filtering, drying, obtains off-white powder 17.1g, yield 75.3%, purity 98.4%.

Claims (4)

1. a kind of synthetic method of hydrobromic acid Vortioxetine, it is characterised in that comprise the following steps：
Step 1, ortho-nitrophenyl thiophenol and 2,4- dimethyl halogeno-benzene are condensed to yield 2- (2,4- dimethyl in the presence of acid binding agent Phenylsulfartyl）Nitrobenzene；
Step 2,2- (2,4- 3,5-dimethylphenyl sulfenyls）Nitrobenzene obtains 2- (2,4- 3,5-dimethylphenyls through reduction in acid condition Sulfenyl）Aniline；
Step 3,2- (2,4- 3,5-dimethylphenyl sulfenyls）Aniline and two (2- chloroethyls）Amine hydrochlorate cyclization obtains Vortioxetine；
Step 4, Vortioxetine produces hydrobromic acid Vortioxetine with hydrobromic acid into salt；
Acid binding agent used is sodium hydride, calcium hydride or lithium hydride in step 1；Solvent for use is tetrahydrofuran, 2- methyl tetrahydrochysenes Furans or dioxane；
In step 1, it is necessary to carry out that solution plus toluene and water progress extraction processing is evaporated off successively to reactant after reaction terminates；
In step 1,2,4- dimethyl halogeno-benzenes are selected from 2,4- dimethyl iodobenzene or 2,4- dimethyl bromobenzene；
In step 1, the molar ratio range of ortho-nitrophenyl thiophenol, 2,4- dimethyl halogeno-benzene and acid binding agent is 1：0.7~1.4：0.8 ~1.5；
In step 2, reducing agent used is iron, zinc or tin；The acid condition is ammonium chloride solution.
2. the synthetic method of hydrobromic acid Vortioxetine according to claim 1, it is characterised in that：In step 2,2- (2,4- 3,5-dimethylphenyl sulfenyl）The molar ratio range of nitrobenzene and reducing agent is 1：2~6,40~70 DEG C of reaction temperature, reaction time 1 ~10 hours.
3. the synthetic method of hydrobromic acid Vortioxetine according to claim 1, it is characterised in that：Solvent for use in step 3 For toluene, dimethylbenzene or acetonitrile.
4. the synthetic method of hydrobromic acid Vortioxetine according to claim 1, it is characterised in that：2- (2,4- bis- in step 3 Aminomethyl phenyl sulfenyl）Aniline and two (2- chloroethyls）The mol ratio of amine hydrochlorate is 1：0.8~1.2.
CN201510758811.2A 2015-11-10 2015-11-10 A kind of synthetic method of hydrobromic acid Vortioxetine Active CN105348220B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510758811.2A CN105348220B (en) 2015-11-10 2015-11-10 A kind of synthetic method of hydrobromic acid Vortioxetine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510758811.2A CN105348220B (en) 2015-11-10 2015-11-10 A kind of synthetic method of hydrobromic acid Vortioxetine

Publications (2)

Publication Number Publication Date
CN105348220A CN105348220A (en) 2016-02-24
CN105348220B true CN105348220B (en) 2017-08-25

Family

ID=55324305

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510758811.2A Active CN105348220B (en) 2015-11-10 2015-11-10 A kind of synthetic method of hydrobromic acid Vortioxetine

Country Status (1)

Country Link
CN (1) CN105348220B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107266390A (en) * 2017-08-07 2017-10-20 山东鲁宁药业有限公司 A kind of new technique for synthesizing of hydrobromic acid Vortioxetine
CN111320592A (en) * 2018-12-17 2020-06-23 天津理工大学 Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine
CN113651738A (en) * 2021-08-18 2021-11-16 苏州大学 Preparation method of diphenyl sulfide compound
CN115368318B (en) * 2022-06-22 2023-11-03 山东辰龙药业有限公司 Synthesis method and application of voathixetine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230852A (en) * 2014-08-29 2014-12-24 成都倍特药业有限公司 Synthetic method of vortioxetine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103788019B (en) * 2014-01-22 2015-10-07 苏州明锐医药科技有限公司 The fertile preparation method for Xi Ting
CN104130212B (en) * 2014-07-01 2016-08-24 安徽省逸欣铭医药科技有限公司 A kind of applicable hydrobromic acid irrigates the synthetic method for western spit of fland industrialized production
CN104650004B (en) * 2015-03-06 2017-06-06 中山万汉制药有限公司 A kind of preparation method of hydrobromic acid Vortioxetine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230852A (en) * 2014-08-29 2014-12-24 成都倍特药业有限公司 Synthetic method of vortioxetine

Also Published As

Publication number Publication date
CN105348220A (en) 2016-02-24

Similar Documents

Publication Publication Date Title
CN105348220B (en) A kind of synthetic method of hydrobromic acid Vortioxetine
EP2170805B1 (en) Methods of synthesizing cinacalcet and salts thereof
CN103788019B (en) The fertile preparation method for Xi Ting
CN105283442A (en) New process for the synthesis of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine
JP5873484B2 (en) Dronedarone and method for producing the salt thereof
CN101062897B (en) Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof
AU2015229742A1 (en) Clomiphene synthesis using a single solvent
JP2000063334A (en) New intermediate for producing eneyne derivative and its production
CN104829557B (en) A kind of noval chemical compound 1 [2（2,4 3,5-dimethylphenyl sulfenyls）Phenyl] 2 oxygen piperazines and preparation method thereof and the application in Vortioxetine synthesis
CN103923058B (en) A kind of method synthesizing Wei Lanteluo intermediate and salt thereof
CN114773176B (en) Chlorpheniramine maleate impurity and preparation method and application thereof
CN110818678B (en) Method for preparing cyclohexane derivative
CN107216271A (en) Tartaric acid Mo Fanselin impurity and preparation method thereof
CN106831610B (en) A kind of catalysis oxidation synthetic method of quinazoline compounds
CN103183680A (en) Method for preparing asenapine
CN107043355B (en) A kind of hydrochloric acid Emedastine midbody compound and preparation method thereof
CN103130782B (en) Hydroxylamine hydrochloride is prepared the method for Lafutidine
WO2014008639A1 (en) Method for preparing indacaterol
EP2739610B1 (en) Process for the manufacture of ivabradine and of intermediates of synthesis thereof
EP3704116B1 (en) Process for the synthesis of 2-benzhydryl-3 quinuclidinone
WO2012085645A1 (en) Polymorphs of 3-chloro-4[(2r)-2
CN103922996B (en) A kind of drug new intermediate and preparation method thereof
CN105859683B (en) The high-purity technical preparation process of Imatinib
CN106831652B (en) A kind of preparation method of Wo Saiting
US9000165B2 (en) Process for the preparation of anhydrous aripiprazole crystal form II

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address

Address after: 252022 north head of Lushan Road, Liaocheng Development Zone, Shandong Province

Patentee after: Shandong Chuan Cheng Medicine Co.,Ltd.

Address before: 252022, Shandong, Liaocheng economic and Technological Development Zone, Jin Shan Road North Head

Patentee before: SHANDONG CHUANCHENG PHARMACEUTICAL Co.,Ltd.

CP03 Change of name, title or address